JPS6021995B2 - Method for producing penicillin esters - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pannicillin ester and a method for producing its sulfoside.

The novel pan-nichirine ester of this invention has the following general formula (
1).

(In the formula, A is an acylamido group, R is a lower alkyl group or
The sulfoxide of this invention has the above general formula ( 1) is the S-oxide, which is also a substance with extensive literature.

Until now, many penicillin esters have been known,
The purpose of producing the ester is to convert 'a' natural penicillin into an ester form, convert the 6-position acyl group, deesterify it, and use it to produce a new penicillin. is converted into an S-oxide form, followed by a ring conversion reaction to form a 7-acylamido-3-deacetoxycephalosporanic acid ester, which is then deesterified or after converting the acyl group at the 7-position, deesterified. {c' Natural penicillin is converted into an ester form, the 6-position acyl group is converted, and the resulting penicillin ester is used as a product with increased absorbability when administered orally.

etc. can be mentioned.

Therefore, unless the ester itself is used as a medicine, the ester must be deesterified at the penicillin or cephalosporin derivative stage after the necessary chemical reactions.

Since the deesterification must be carried out mildly under conditions that do not involve cleavage of the 8-lactam ring, the types of ester groups are extremely limited. In particular, in the case of cephalosporin esters after ring conversion from penicillin esters, the deesterification conditions involve movement of double bonds, so in order to obtain △3, which is useful as an antibiotic, deesterification is necessary. Reactions have also been extremely limited. The inventor of this invention took such a deesterification reaction into consideration and discovered a new ester group that is capable of carrying out the desired reaction and deesterification reaction and is industrially valuable. It's arrived. This invention provides a penicillin or a salt thereof represented by the general formula (wherein A has the same meaning as above);
2 is a lower alkyl group or a Q-halogenoacetoacetic acid derivative represented by (which may be ring-closed with a bonded nitrogen atom and an oxygen atom to form a morpholino group) is reacted to form a penicillin ester;
It can be produced by treating this with an oxidizing agent as necessary to form the corresponding sulfoxide.

Any acylamide group at the 6-position of the penicillin represented by the above general formula (1) can be used.

Examples include phenylacetamide group, phenoxyacetamide group, acetamide group, propionamide group, benzoylamino group, phthalimide group, 2-trichloroethoxycarbonylamino group, and benzyloxycarbonylamino group, but from an industrial standpoint, , a phenylacetamide group and a phenoxyacetamide group are preferred. Salts of penicillin of general formula (1) include potassium salt, sodium salt,
Triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N-methyl-morpholine salt, morpholine salt, piveridine salt, N-ethylpiveridine salt, N
-methylpiveridine salts, etc., but potassium salts and sodium salts are usually preferred.

Q-halogenoacetoacetic acid derivative (m) used in this invention
Preferred specific examples include methyl Q-bromoacetoacetate, ethyl Q-bromoacetoacetate, Q-bromoacetoacetic acid isobutyl ester, Q-bromoacetoacetic acid N·N-dimethylamide, Q-bromoacetoacetic acid N·N-jethylamide, Q-bromoacetoacetate Acetic acid N・N-dipropylamide, N-(Q-bromoacetoacetyl)morpholine, N
-(Q-promoacetoacetyl)piveridine and their chlorides.

In the esterification reaction of this invention, an inert solvent is usually used, and penicillin of the general formula (0) or a salt thereof is mixed with the general formula (m
) by reacting the Q-halogenoacetoacetic acid derivative.

When using penicillin itself of general formula (0), it is preferable to add a base such as triethylamine or N-methylmorpholine to the reaction system in advance to convert penicillin into a salt form and react. Inert solvents used include methanol, ethanol, butanol, acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl propyl ketone,
Methyl isoptyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, trichlorethylene, trichlorethane, propylene chloride, ethylene glycol dimethyl ether, Examples include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, etc.
Among these, preferred examples include dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, methyl isobutyl ketone, methyl isopropyl ketone, methyl ethyl ketone, methylene chloride, trichloroethylene, and ethylene chloride.

The reaction is carried out at 0 to 100 qo, usually from 10 to 60 qo.

The reaction time varies depending on the reaction temperature, the type of solvent, the type of halogen in the compound of general formula (m), etc. When a chlorine compound is used as the halogen in the Q-halogenoacetoacetic acid derivative (m), the reaction can be accelerated by adding a catalytic amount of potassium iodide to the reaction system, if necessary. The progress of the reaction can be tracked and confirmed by TLC (thin layer chromatography) (e.g., developed with benzene:ethyl acetate = 2:1 and developed with azide iodide).

After the reaction is completed, the solvent is removed from the reaction solution if necessary, ice water is added to the residue, and the product is extracted with the solvent. Extraction solvents include methyl acetate, ethyl acetate, butyl acetate, methylene chloride, chloroform, ethylene chloride, benzene, toluene, xylene, ethyl ether, isopropyl ether, isobutyl ether, methyl isobutyl ketone,
Methyl isopropyl ketone, butanol, etc. can be used. The products obtained by removing the solvent from the extract are either crystalline or oily. The product thus isolated can be dissolved in an appropriate solvent or the esterification reaction solution described above can be oxidized with an oxidizing agent to yield the corresponding sulfoxide.
As the oxidizing agent, those commonly used in the art of penicillin and cephalosporin can be used. Examples include peracetic acid, perbenzoic acid, methachloroperbenzoic acid, hydrogen peroxide, and the like. In addition, oxyacid salts such as vanadium, molybdenum, and tungsten are added as catalysts,
It may be advantageous to perform a reaction. Preferable solvents used here include dimethylformamide, dimethylacetamide, acetone, methanol, methyl isobutyl ketone, methyl isopropyl ketone, and acetonitrile.
After the reaction is completed, the desired sulfoxide can be isolated by adding, for example, ice water to the reaction and performing a solvent extraction process.

The novel pannicillinester sulfoxide obtained here is generally crystalline. The object of this invention is particularly useful as a synthetic intermediate for penicillin and cephalosvorin, and after performing the desired reaction, the ester moiety and S
-The oxide moiety can be removed very easily and with high yields. Although it is thought that the Q-halogenoacetoacetic acid derivative, which is a raw material of this invention, exists in a keto type and an enolic type, in this invention, the keto type is expressed using the general formula (m) for convenience.

On the other hand, the magnetic resonance spectrum of the target product revealed that it generally contains approximately half the keto form and the enolic form; however, this invention is expressed as the keto form for convenience. Next, this invention will be explained by examples.
The invention is not limited thereby.

Example 1 One part of pendylbenicillin potassium salt and one part of acidic potassium carbonate were suspended in 40 parts of acetone, 40 parts of dimethyl sulfoxide and 4 parts of dimethylformamide,
At room temperature, Q-chloroacetoacetic acid methyl ester was added dropwise within 30 minutes.

After completing the dropping, the inside of the dropping funnel was washed with 10wZ of acetone, added to the reaction solution, and reacted while holding a light. The reaction solution gradually takes on a fringe color. TLC (benzene: ethyl acetate: 2:1
, azide iodide heating color development). If necessary, the reaction solution is heated to 40-50 qo in a water bath. The reaction is completed in 4 to 6 hours. After distilling off the acetone under reduced pressure, 100 parts of ethyl acetate and 200 parts of ice water were added to adjust the pH to 7.3 under Koji Azusa, and the organic layer was separated. The aqueous layer was extracted several times with ethyl acetate, the organic layer was combined, washed with water, and dried over magnesium sulfate.
The solvent is distilled off. The residue did not solidify even though it was treated with methylene chloride and n-hexane. Separate the oil layer and remove the solvent under reduced pressure. 6-phenylacetamide-benicillanic acid (
1-Methoxycarbonyl)-2-oxopropyl ester was obtained in a yield of 44 mm (% spot).

Example 2 Penzylbenicillin potassium salt and acidic potassium carbonate salt were suspended in a mixture of 60 parts of acetone and 50 parts of dimethylformamide, and the solution was suspended with Q-chloroacetoacetic acid methyl ester at room temperature within 3 minutes. Add it dropwise, and wash the inside of the dropping funnel with 5 parts of acetone and add to the reaction solution.

Heat the rope to 45-55°C in a water bath. After confirming the completion of the reaction by TLC (benzene:ethyl acetate=2:1, color development by heating with azide iodide), acetone was removed under reduced pressure and the mixture was cooled on ice. The esterification reaction required about 5 hours. 40% of calculation amount
Oxidize with acetic acid. The oxidation reaction is monitored by TLC (benzene: ethyl acetate = 1:1), and if necessary, peracetic acid is added to complete the reaction. Add 200 ml of ethyl acetate and 200 ml of ice water to the reaction, and add ammonium carbonate under coagulation.
．． 3, separate the organic skin, and extract the aqueous layer several times with ethyl acetate. The organic layer is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue is cilantro. It solidifies when treated with isopropyl ether. Recrystallization from ethanol and isopropyl ether yielded the sulfoxide of 6-phenylacetamidobenicillanic acid-(1-methoxycarbonyl)-2-oxopropylester with a melting point of 124-12yC (94%). I got it from Infrared absorption spectrum: 18
0-lactam-1 (8-lactam).

Example 3 Q-chloroacetoacetic acid ethyl ester is used in place of Q-chloroacetoacetic acid methyl ester in Example 2, and the reaction and treatment are carried out according to Example 2.

A sulfoxide of 6-phenylacetamidobenicilanic acid-(1-ethoxycarbonyl)-2-oxopropyl ester was obtained in the form of a syrup.

Yield 43 evenings (90%). Example 4 Phenoxymethylbenicillin potassium salt 39 was used instead of penzylbenicillin potassium salt in Example 2, and the reaction was carried out according to Example 2.

A sulfoxide of 6-phenoxyacetamide-benicillanic acid-(1-methoxycarponyl)-2-oxopropylester was obtained in a yield of 44 min (92%).

Recrystallize from inpropyl alcohol and isopropyl ether. Melting point: 65-670. Infrared absorption spectrum: 1800 skin-1 (8-lactam). Example 5 In place of Q-chloroacetoacetic acid methyl ester in Example 2, Q-chloroacetoacetic acid methyl ester was used, and the reaction and treatment were carried out according to Example 2.

However, the reaction rate of the bromine compound was faster than that of the chloro compound, and the reaction was completed in 5 to 6 hours at room temperature. 6-phenylacetamidobenicilanic acid-(1-methoxycarbonyl)-2-oxopropyl ester sulfoxide at 93%
% yield.

Melting point: 124-12500 (recrystallized). It was consistent with the product obtained in Example 2. Example 6 A suspension of pendylbenicillin potassium salt and an acidic potassium carbonate salt was suspended on 70% of dimethylformamide, and the solution was stirred at room temperature. Add 30' of Mido solution dropwise.

After the dropping is completed, keep the temperature at 4-0 on the top of the Kagami Azusa Mizuhiro and let it react. T
Follow up with LC to confirm the completion of the reaction. 4. Calculations under ice cooling
Oxidize with 0% peracetic acid. Follow up with TLC (benzene: ethyl acetate = 1:1, azide dichloride heat color development) to confirm the completion of the reaction, add 100 parts of methylene chloride and 200 parts of ice water, and adjust the pH to 7.2 with acidic sodium carbonate. Separate the organic layer, extract the water layer several times with methylene chloride, combine the organic layers, wash with water, and dry. The solvent is removed under reduced pressure. The sulfoxide of 6-phenylacetamide-benicillanic acid-(11N.N-dimethylaminocarbonyl)-2-oxopropyl ester is obtained in the form of a sill.

Yield: 42.5 evenings (92%). It crystallizes when treated with inpropyl alcohol and isopropyl ether. Melting point:
52-5500. Infrared absorption spectrum: 1800 skin-
10 Example 7 Penzyl Benishi IJ potassium salt and acidic potassium carbonate were suspended in 50 parts of dimethyl sulfoxide and 40 parts of dimethylformamide to give Nawaazusa Q-chloro-N.
N-dimethyl-acetoacetamide was added dropwise and the reaction temperature was maintained at 40-60°C, and the reaction was monitored by TLC.

If necessary, add a catalytic amount of sodium chloride. 5
The reaction is completed in ~7 hours.

After cooling, add 150 parts of methylene chloride and 200 parts of ice water to adjust the temperature to 7.2 cm, and separate the organic layer. Add salt to the aqueous layer and extract several times with methylene chloride. Combine the organic layers, wash with water, and dry. The solvent is removed under reduced pressure.

Dissolve the residue in methanol, add a catalytic amount of vanadium pentoxide, and oxidize with a calculated amount of 30% aqueous hydrogen oxide. T.L.
C, and if necessary, add an oxidizing agent to complete the reaction. Add 50 ml of ice water, adjust to 7.3 ml, and remove methanol under reduced pressure. The aqueous layer containing the precipitate is extracted with methylene chloride, and the organic layer is washed with water, dried, and the solvent is removed. It solidifies when treated with isopropyl ether. Melting point after recrystallization from inpropyl alcohol and isopropyl ether:
The same product as Example 6 of 52-55q0 was obtained. Yield 42
Evening (91%). Example 8 Phenoxymethylbenicillin potassium salt was used in place of penzylbenicillin potassium salt in Example 6, and the reaction and treatment were carried out according to Example 6.

Recrystallization from ethanol and isopropyl ether yields the sulfoxide of 6-phenoxyacetamide-benicillanic acid mono(11N.N-dimethylaminocarbonyl)-2-oxopropylester with a melting point of ~6〆○. was obtained in a yield of 91%. Infrared absorption spectrum: 1800M-10 Example 9 Penzylbenicillin potassium salt 19 minutes and acidic sodium carbonate salt 0.5 hours were suspended in 30 minutes of dimethylformamide, and then suspended in 30 minutes of dimethylformamide. Add and react on a water bath at 40°C.

Follow the reaction with TLC. After the reaction, methylene chloride 10
Add 0' and oxidize with 40% peracetic acid. Add 100ml of ice water to the reaction solution and adjust the pH to 7.3.
The organic layer is separated and the aqueous layer is extracted several times with methylene chloride. The organic layers are combined, washed with water, and dried. The solvent is removed under reduced pressure. The residue is syrup. 6-phenylacetamidobenicilanic acid-(11morpholinocarbonyl)-2-oxof. 21 pieces of sulfoxide of lopilester were obtained. Recrystallization from inpropyl alcohol and isopropyl ether gave a product with a melting point of 70 to 80 qo. Infrared absorption spectrum: 180 cucumber-1.

Example 10 Phenoxymethylbenicillin potassium salt was used in place of penzylbenicillin potassium salt in Example 9, and the reaction was carried out according to Example 9 to produce 6-phenoxyacetamidobenicillanic acid-(1-monophoricarponyl)-1. A sulfoxide of 2-oxypropyl ester was obtained.

Yield 92%. Melting point 80-10000. Infrared absorption spectrum: 180-1. Reference Example 1 6-phenylacetamide benamoo 3-carboxylic acid 11'-methoxycarbonyl-2-oxopropyl (1') obtained in Example 1
- ester-1-oxide 4.15% and chloromethylphosphonic acid pyridine salt 73% are reacted in anhydrous dioxane 30°C at ~101°C under heating.

Follow the reaction with thin delivery croftography. The reaction is completed in 4 to 7 hours, so the mixture is cooled and the solvent is distilled off under reduced pressure.

Add methylene chloride and water to the residual liquid, adjust the pH to 7.0 to 7.5, and separate the organic layer. The aqueous layer is extracted several times with methylene chloride, and the methylene chloride layer is washed with brine and dried. Divide the methylene chloride solution into two parts.

1 minute Remove the solvent under reduced pressure.

Solidify with ethyl acetate + n-hexane. 7-phenylacetamide-3-methyl-3-cephemu 4-carboxylic acid (1'-methoxycarbonyl)-2-oxopropyl(1')-ester melting point 110-120 qo 1.8
1 night (81%).

Purified by silica gel chromatography (benzene: ethyl acetate = 4:1), melting point 119-12 ○, infrared absorption spectrum 176 & 1 (8-lactam), ultraviolet absorption spectrum ^ma x 25 ratio. While cooling the methylene chloride solution with ice, add a few drops of sodium tungstate aqueous solution or vanadium pentoxide aqueous solution to 40%
Peracetic acid 0.7M is slowly added dropwise.

Follow up with thin layer chromatography and add peracetic acid if necessary. After the reaction is complete, add ice water and drain with ammonia water7.
5 and separate the organic layer. The aqueous layer is extracted several times, combined, washed with brine, dried, and the solvent is removed under reduced pressure. Qianzumi is treated with isopropanol-n-hexane to solidify it. melting point 14
4-470 (Decomposition) 7-phenylacetamide-3-methyl-3-cephemu-4-carboxylic acid mono(r-methoxycarbonyl)-2-oxopropyl-(1')-ester-1-oxide for 1.97 days (85%) Obtained. Purified by silica gel chromatography (ethyl acetate), melting point 16
9-170℃ (decomposition), infrared absorption spectrum 177&
Water-1, ma x 254n machine with ultraviolet absorption spectrum. Then, 7-phenylacetamido-3-methyl-3-cephemu-4-carboxylic acid-1'-methoxycarbonyl-2
- Add 4.5 parts of oxopropyl(1') ester to a mixture of 30 parts of acetone and 20 parts of water and cool with water.

Drop 2.7 drops of butyl nitrite under the rope. A reaction will occur soon. To this, 1.7 hours of sodium acetate and 1 hour of acetic acid were added in several portions, and the mixture was gradually warmed to a temperature of 40 to 50
oo for 30 minutes. The reaction is followed by TLC. Add butyl nitrite and acetic acid if necessary. After confirming the completion of the reaction, add 10w' of water and adjust the pH to 7.5.
and remove acetone under reduced pressure. The aqueous layer was washed several times with ethyl acetate and adjusted to an axis of 2.0 with Nawa Azusa hydrochloric acid. The crystals are collected, washed with water, and dried. The mother liquor and washings are combined and extracted several times with ethyl acetate. The ethyl acetate layers were combined and washed several times with brine, dried, and the solvent was removed under reduced pressure. A total of 3.16 units (95%) of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid was obtained.

Claims (1)

[Claims] 1 Penicillin or its salts represented by the general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (A in the formula means an acylamide group) The general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X is a halogen atom, R is a lower alkoxy group, or a ▲ mathematical formula, chemical formula, table, etc.), and R_1 and R_2 are lower alkyl groups or ring-closed together with the bonded nitrogen and oxygen atoms to form a morpholino group. may be formed) to obtain a penicillin ester represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, each symbol has the same meaning as above) A method for producing penicillin esters, characterized by: 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A means an acylamido group) Penicillin or its salts have a general formula ▲ Numerical formula, chemical formula, tables, etc. ▼ (In the formula, X means a halogen The atom, R, means a lower alkoxy group or a ▲ mathematical formula, chemical formula, table, etc. ) is reacted with the α-halogenoacetoacetic acid derivative to obtain a penicillin ester represented by the general formula ▲Mathematical formula, chemical formula, table, etc.▼ (in the formula, each symbol has the same meaning as above), which is then treated with an oxidizing agent. 1. A method for producing penicillin esters, which comprises converting the esters into the corresponding sulfoxides.